Continuous advances in cancer research greatly depend on development of valid animal models. However, only few genetically modified mice exist in which metastatic stage of carcinogenesis can be accurately reproduced. A need for such models is extremely high, because metastatic progression is the most lethal feature of advanced cancer. Modeling and targeting metastasis are long-term goals of the Pl Recently, we have described spontaneous metastasis of thyroid C-cell carcinomas developing in mice with a single wild-type copy of the retinoblastoma susceptibility gene (Rb). In that model initial stages of metastatic disease can be alleviated by reconstituting Rb function. These results are in a good concordance with other studies indicating that Rb might contribute to such metastasis-relevant cell properties as motility, adhesion, and invasion. Of clinical importance, aberrations in Rb or Rb-mediated pathways are often observed in advanced human cancers, including small cell carcinoma of the lung. Unfortunately, careful characterization of the metastatic model associated with Rb inactivation has been impossible because majority of Rb+/- mice succumb to tumors of the pituitary intermediate lobe before development of extensive C-cell metastasis. Recently, several mouse genetic systems have been described, which allow for conditional inactivation of genes in temporal, spatial and cell type-specific fashion. By applying these systems we propose to (1) prepare mouse models allowing selective inactivation of Rb in thyroid C-cells, (2) test the hypothesis that C-cell specific inactivation of Rb results in development of overt metastasis during thyroid C-cell carcinogenesis, and (3) test the hypothesis that reconstitution of Rb expression will attenuate metastatic progression. It is expected that success of these studies will result in development of new and accurate animal models, allow for better understanding of Rb roles in metastatic process, and provide the most rigorous proof of RB-mediated suppression of metastasis in vivo. Thus, a solid foundation will be provided for design and testing therapeutically relevant approaches to rational gene targeting of advanced cancer associated with Rb deficiency.